Thermosensitive Progesterone Hydrogel: A Safe and Effective New Formulation for Vaginal Application

PURPOSE: The safe and functional delivery of progesterone through the vaginal route remains an unmet clinical need. The purpose of this work is to prepare a new progesterone (P4) gel for vaginal application using a thermosensitive mucoadhesive polymer, glycol chitin (GC). METHOD: Thermogelling, mucoadhesive, mechanical, and viscoelastic properties of GC and the new formulation were evaluated using rheometry. In vitro release profile and the bioactivity of P4 were determined using vaginal fluid simulant (VFS) pH 4.2, and PR-reporter gene assay, respectively. In vitro safety of the formulations was tested using (VK2/E6E7) vaginal epithelial cell line and Lactobacillus Crispatus. Finally, in vivo safety and the efficacy of this formulation were evaluated using an endometrial hypoplasia mouse model. RESULTS: Results shows the aqueous solution of 5%; (w/v) GC loaded with 0.1%; (w/v) P4 prepared in pH 4.2, (GC-P4), forms a thermosensitive mucoadhesive hydrogel and can maintain stable physical properties at 37°C. GC-P4 gel release 50% of P4 in 4 h after exposure to VFS, and no significant decrease in % viability of VK2/E6E7 or Lactobacillus was found after exposure to 5% GC or GC-P4. GC-P4 does not exhibit obvious toxicities to vaginal tissue in vivo even after repeated application. Efficacy studies indicated that GC-P4 was capable of preventing the progression of simple endometrial hyperplasia (SEH) to complex atypical endometrial hyperplasia (CAEH) in vivo. CONCLUSIONS: Results indicates that GC-P4 retains many characteristics for an effective vaginal delivery system for P4. Therefore we believe that GC-P4 formulation is a promising alternative to current vaginal P4 formulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11095-014-1616-8) contains supplementary material, which is available to authorized users.